Therapeutically, an antagonist that possesses both kinase selectivity for protein kinase C (PKC) and PKC isozyme selectivity is a potentially useful pharmacological agent. Hartenstein, J. H. et al., "Perspectives in Medicinal Chemistry," 99-118 (1993), VCH Publishers, New York. Such an antagonist of protein kinase C would be useful in treating disease states in which PKC has been implicated. Lester, D. S., et al., "Protein Kinase C: Current concepts and Future Perspectives", Ellis Horwood New York (1992). Specific isozymes of protein kinase C have been implicated in cancer (Ahmed, et al., Mol. Pharma., 43, 858-86 (1993), CNS diseases such as Alzheimer's (Demaerschalck, et al., Biochem. Biophys. Acta. 1181, 214-218 (1993)), cardiovascular disease (Natarajan et al. Mol. Cell. Endo., 101, 59-66 (1994)) and diabetic complications (King, et al., Proc. Nat. Acad. Sciences (USA), 88:22, 11059-63 (1992)).
Recently, a class of compounds, referred to herein as bis-indolylmaleimides, have been identified as potent and effective inhibitors of PKC. Compounds within this class are described, for example, in Davis et al., U.S. Pat. No. 5,057,614 (1991), Barth et al., European patent Application 397 060 (1992), Schultz et al., in PCT application WO 91/13070, Barth et al., U.S. Pat. No. 5,380,746, U.S. patent application Ser. No. 08/163,060, abandoned, U.S. patent application Ser. No. 08/324,948, and U.S. patent application Ser. No. 08/316,973, abandoned. This class of compound is generally represented by Formula I: ##STR3## wherein X, Y and R represent optional substitutions.
The present invention provides a novel process for preparing compounds of the Formula I. More specifically, the invention provides an efficient process for reacting a bis-alpha-keto indolyl acid of the Formula II: ##STR4## wherein R.sup.1 is a hydrogen, C.sub.1 -C.sub.4 alkyl or benzyl, and R, X, and Y are optional substitutions; to produce a novel bis-indolylmaleic acid of the Formula III: ##STR5## Compounds of the Formula III are readily converted to the bisindolylmaleimide of Formula I.
Reductive dimerization with ketones and aldehydes to yield olefins on treatment with low-valent titanium reagents is known in the art and generally described in J. E. McMurry, Chem. Rev. 89: 1513-24 (1989). The reaction is also described in J. E. McMurry et al., J. Am, Chem. Soc. 105:1660-61 (1982), which demonstrates keto ester cyclization under similar conditions. However, before the present invention, it was unknown that low valent titanium effectively couples alpha keto indolyl acids of the Formula II. Thus, under the conditions described herein, the compounds of Formula I may be produced in an efficient process at high yield.